Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people over the age of 50. Diabetic retinopathy (DR) is the most common cause of blindness in young and middle-aged people. Clinical or animal models demonstrated that VEGF/KDR or PDGF/PDGFR-β was abnormally high in the diseased tissues. The severity of choroidal or retinal pathological neovascularization was significantly positively correlated with the level of VEGF/KDR expression in the diseased tissues. Anti-VEGF antibodies or tyrosine kinase inhibitors can effectively inhibit the formation of neovascularization. Inhibiting the phosphorylation of KDR and PDGFR receptor tyrosine kinase as a target for drug development has become the newest strategy for the treatment of ocular neovascularization. VEGFR receptors are mainly expressed in vascular endothelial cells and tumor cells. Vascular endothelial growth factor receptor-2 (KDR) plays a key role in the formation of neovascularization. VEGFR receptors mainly expressed in endothelial cells and tumor cells. Novel naphthylurea derivatives ascular endothelial growth factor receptor-2 (KDR) plays a key role in the formation of new blood vessels. PDGFR receptors mainly express in vascular wall cells. PDGFR-β receptor plays a major role in maintaining the integrity of the blood vessel wall. VEGF or PDGF growth factor produces biological effects by the phosphorylation of receptor kinase thereof. Lucentis fails to meet clinical needs. 60% of wet AMD patients still fail to respond to Lucentis therapy, and need intraocular injection once a month resulting in potentially serious ocular complications. The efficacy of anti-VEGF-only therapy is limited. The price of Lucentis is very expensive, and a patient needs 12 injections every year and pays an annual payment of 28000 US dollars (about 180000 China Yuan). Therefore, developing a reliable, easily administrating and cheaper drug has become one of the objectives of the major pharmaceutical companies in the world. It is also one of the medical application blanks desired to be filled.
Clinical and scientific researches have fully proved that abnormal KDR expression and intracellular signal transduction play an important role in formations of pathological choroidal or retinal neovascularization. After KDR binding with its specific ligand VEGF, receptor tyrosine kinase is autophosphorylated and induces a series of intracellular signal transduction, resulting in the proliferation and migration of vascular endothelial cells and angiogenesis. Therefore, inhibiting the phosphorylation of KDR receptor tyrosine kinase can effectively block the abnormal intracellular signal transduction induced by KDR, and reduce pathological choroidal or retinal neovascularization, and thereby prevents the severe visual loss caused by choroidal or retinal bleeding, scarring and fibrosis induced by neovascularization. For example, Drug Lucentis or Macugen (both are VEGF antibodies) approved by the United States FDA presently is used for the treatment of age-related macular degeneration. Moreover, clinical data has demonstrated that intraocular injection of Lucentis or Macugen can effectively prevent the eyesight of patients with age-related macular degeneration from further fading by inhibiting the VEGF/KDR expression-induced abnormal intracellular signal transduction. In addition, PDGFR also involves in the formation of neovascularization and inhibits phosphorylation of PDGFR receptor tyrosine kinase, which can cause the auto-apoptosis of perithelial cells of the pathological choroidal or retinal neovascularization reluting in degenerative changes and atrophies of the pathological new vessels such that vision is effectively improved. Therefore, drug designs targeting to control VEGF/KDR and/or PDGF/PDGFR abnormal expression and signal transduction have become new strategies of treating age-related macular degeneration and diabetic retinopathy.
In addition, the occurrence, development and metastasis of many tumors and the formation of tumor neovascularization are closely related with the abnormal expression of tyrosine kinase. Particularly, some tyrosine kinase receptors abnormally express in solid tumor cells, wherein vascular endothelial cell growth factor receptor (VEGFR) highly expresses both in many tumor cells and tumor vascular endothelial cells, and platelet-derived growth factor receptor (PDGFR) abnormally expresses in tumor stromal fibroblasts. The autocrine loop formed by ligands and receptors of tyrosine kinase directly participates in the occurrence and development of tumor cells, for example, vascular endothelial cell growth factor receptor (VEGFR) exist in melanoma; platelet-derived growth factor receptor (PDGFR) exist in glioma; and stem cell growth factor receptor (KIT) exist in small cell lung cancer, and the like. In addition, similar loops exist in melanoma, meningioma, neuroendocrine tumors, ovarian cancers, prostate cancers, lung cancers and pancreatic cancers. These loops closely link with the occurrence and development of tumors. Stem cell growth factor (Kit) is ligand of stem cell growth factor receptors (SCFR, c-KIT). KIT/SCFR have a very close relationship with hematopoietic function of body, and development of mast cells and Cajal interstitial cells. The study found that there are more than 30 function-acquired mutation versions of KIT/SCFR, which are the direct inducements of occurrence and development of many tumors. Furthermore, the autocrine loop of KIT/SCFR exists in 70% of patients with small cell lung cancer, and helps the cancers to develop independent of growth factors. In addition, the occurrence, development and metastasis of solid tumors are dependent on formation of tumor neovascularization which provides essential nutrients and oxygen for the growth of tumor. Tumor angiogenesis is an important process for invasion, migration and proliferation of cancer cells. Vascular endothelial cell growth factor receptor (VEGFR) family and platelet-derived growth factor receptor (PDGFR) family are directly related with occurrence and development of tumor and formation of tumor angiogenesis. Vascular endothelial growth factor (VEGF), known as the most powerful vascular penetrant and endothelial cell-specific mitogen, plays an important role in proliferation, migration and angiogenesis of endothelial cells. The expression level of VEGF shows an obviously positive correlation with the vascularization degree of tumor tissue. VEGF mainly acts on high affinity receptors VEGFR-1 and KDR in endothelial cells which have different signal transduction pathways such that tyrosine kinase is phosphorylated to play its biological action. KDR plays a key role in growth, metastasis and angiogenesis of tumor. Platelet-derived growth factor (PDGF) and its receptor (PDGFR) involve with pathogenesis of multiple tumors, and play important roles in angiogenesis. Platelet-derived growth factor (PDGF) shows its cell biological effects via its receptor (PDGFR). PDGFR maintains the integrity of the vascular wall and promotes the formation of tumor neovascularization by regulating the proliferation and migration of vascular wall perithelial cells and vascular smooth muscle cells. Moreover, the growth of tumor is promoted by changing the microenvironment within tumor.
Due to the abnormal expression of tyrosine kinase is closely related with the occurrence, development, metastasis and neovascularization of tumor, drug research and development targeting tyrosine kinase has become a focus of anti-tumor drugs research in the world. Especially, it is a new strategy to treat cancer that targeting neovascularization to inhibit the formation of tumor angiogenesis and block nutrient supply and migration path of tumor to prevent growth and metastasis of tumor. The abnormal expression of KDR or PDGFR receptors plays a key role in the formation of tumor neovascularization, and therefore KDR or PDGFR receptors have become the most ideal target of anti-tumor drug therapy. Furthermore, two anti-tumor drugs Sorafenib and Sunitinib (SU11248) mainly inhibiting KDR and PDGFR receptor tyrosine kinase, approved by the US Food and Drug Administration (FDA), have fully proved their anti-tumor therapeutic effects with high curative effects and fewer side effects in clinical practice.